S198: BET INHIBITOR PELABRESIB (CPI-0610) COMBINED WITH RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS — JAK INHIBITOR-NAÏVE OR WITH SUBOPTIMAL RESPONSE TO RUXOLITINIB — PRELIMINARY DATA FROM THE MANIFEST STUDY
Authors: J. Mascarenhas, M. Kremyanskaya, A. Patriarca, C. Harrison, P. Bose, R. K. Rampal, F Palandri, T. Devos, F. Passamonti, G. Hobbs, M. Talpaz, A. Vannucchi, J.-J. Kiladjian, S. Verstovsek, R. Hoffman, M. E. Salama, D. Chen, P. Taverna, A. Chang, G. Colak, S. Klein, V. Gupta
Journal: HemaSphere (2022)

Background: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (e.g. NF-κB, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. While many MF patients (pts) receive the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) as the current standard of care, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction from BL (TSS50) are limited; thus, a significant unmet medical need exists. Pelabresib (CPI-0610) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB gene expression and other relevant genes involved in MF disease pathways. Aims: Data (Sep 2021 data cut) on the safety and efficacy of pelabresib in combination with RUX in pts with MF from Arms 2 and 3 of the ongoing, open-label Phase 2 MANIFEST study (NCT02158858). In Arm 2, MF pts with suboptimal response to RUX are treated with pelabresib as ‘add-on’ to RUX (Arm 2A: transfusion dependent [TD]; Arm 2B: non-TD). In Arm 3, JAKi-naïve MF pts are treated with pelabresib in combination with RUX. Methods: The primary endpoints are SVR35 at Week (Wk) 24 for Arm 3 and Arm 2B (non-TD cohort) and TD to transfusion independence (TI) in Arm 2A (TD cohort). The key secondary endpoint is TSS50 per Myelofibrosis Symptom Assessment Form v4.0 at Wk 24; in Arm 2A (TD cohort), SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated. Results: At Wk 24 in Arm 3 (N=84), 68% (57/84) pts achieved SVR35 (median change: –50%; Figure), and 56% (46/82) pts achieved TSS50 (median change: –59%). Twenty-four percent of pts had a mean hemoglobin increase ≥1.5 g/dL from BL over 12 weeks without transfusions. At Wk 24 in Arm 2 (N=86), 20% (16/81) pts achieved SVR35 (median change: –18%; Figure), and 37% (30/81) pts achieved TSS50 (median change: –47%). In Arm 2A, the TD to TI rate was 16% (6/38). BM fibrosis improvement by ≥1 grade was achieved in 31% (16/52) and 25% (9/36) pts in Arm 3 and 2, respectively. Further central review and exploratory analyses of BM pathology from a more mature data set, including clinical correlations, will be presented. The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) pts in Arm 3 and 2, respectively. Anemia was reported in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) pts in Arm 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections in Arm 3 and 2 were observed but rarely a reason for treatment discontinuation. Image:Summary/Conclusion: Based on these interim Phase 2 data, pelabresib in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in splenic and symptom responses and BM fibrosis improvement, and appeared to be well tolerated. Based on data from MANIFEST Arm 3, the randomized, double-blind, active-control Phase 3 MANIFEST-2 study was initiated to further evaluate the safety and efficacy of pelabresib in combination with ruxolitinib in JAKi treatment-naïve pts with MF (NCT04603495).